HIV induces a progressive and often irreversible deterioration of the immune system. Through years of experimentation and observation, we have learned that immune responses to HIV do exist and have a range of effectiveness. However, we have also learned about an insidious aspect of the HIV life cycle that enables the virus to persist in the host and to cause immune deterioration. We are referring to the virus'ability to avoid and suppress the immune response. Natural killer (NK) cells are an understudied arm of the immune response against HIV, but are recognized as being crucial in the defense against other viruses. Natural killer cells have the ability to recognize virally infected cells and induce their death via a lytic mechanism, preventing formation of progeny virus particles. Part of the reason that NK cells are not sufficiently studied, in our view, is that HIV infected cells in tissue culture are insensitive to NK killing. In the recent years we have become increasingly aware that the resistance of HIV infected cells to NK is not an accident, but is the result of the combined action of viral proteins that act to suppress the function of NK cells. The viral protein Nef, for example, was the first HIV protein to be found to carry out such a role. The key findings from the laboratories of Drs. Barker and Planelles, which propelled the present studies, show that two other HIV proteins, Vpu and Vpr, manipulate the host cell to also induce resistance to NK lysis. Vpu and Vpr perform this task in a manner that is very distinct from and complementary to that by which Nef acts. The immediate goal of the proposed studies is to understand the mechanisms by which Vpu and Vpr manipulate the sensitivity to NK lysis. The ultimate goal of these studies will be to use this knowledge to devise novel therapeutic approaches aimed at rendering HIV infected cells sensitive to NK killing. PUBLIC HEALTH RELEVANCE: HIV infected cells are resistant to the action of natural killer cells, an important arm of the immune response against many other viruses. Our studies reveal previously unknown activities of viral proteins from HIV-1 that render infected cells resistant to NK recognition and therefore allow HIV to escape this arm of the immune response. We propose to understand the mechanisms by which Vpu and Vpr manipulate the sensitivity to NK lysis. The ultimate goal of these studies will be to use this knowledge to devise novel therapeutic approaches aimed at rendering HIV infected cells sensitive to NK killing.